Abstract Africa is the site of origin of modern humans, contains the greatest levels of human genomic variation, and is the source of the worldwide range expansion of modern humans in the past 100,000 years. However, a fundamental gap in knowledge exists regarding African genomic and phenotypic variation, resulting in a lag in biomedical research, not only in Africans, but also in people of recent African descent. We will apply an integrative evolutionary genomics approach incorporating genomic, metabolomic, microbiome, epigenomic, and transcriptomic data in combination with detailed phenotypic data to reconstruct African population history and better understand the genetic basis of adaptive traits in ethnically diverse African populations. Specifically, we will use genome-wide SNP arrays as well as high-coverage whole genome sequencing data to identify targets of natural selection in these populations and to look for genetic associations with gene expression as well as anthropometric, cardio-metabolic, and immune related traits. We will use functional genomics approaches to identify causal regulatory loci and to study their impact on gene expression in vitro using high-throughput luciferase reporter assays in appropriate cell lines. We will also use Crispr-Cas9 technology to validate and characterize the functional impact of potential casual variants in both human cells and in vivo in model systems. Lastly, we will characterize gut microbiome diversity and examine correlations with diet, genetic and environmental variation. Our data will generate a deeper understanding of African genomic diversity, population structure, and patterns of linkage disequilibrium that are critical for the successful application and interpretation of genome wide association studies in African-descent populations. Furthermore, this study will have important implications for understanding the genetic basis of intermediate phenotypes (gene expression and the metabolome) and of complex traits in Africans. In addition, the data collected will be an important resource for the biomedical research community. Lastly, our study will shed light on human evolutionary history and evolutionary forces shaping patterns of genomic variation in ethnically diverse humans.